1. Field of the Invention
The present invention relates generally to the field of molecular biology, toxicology and oncology. More particularly, it concerns methods for predicting anthracycline cardiotoxicity in patients.
2. Description of Related Art
Anthracyclines, such as Doxorubicin, are still widely used in modern cancer treatments, despite the advent of targeted therapies (Yeh et al., 2009, Force et al., 2011). However, a dose-dependent cardiotoxicity often limits their clinical use. Doxorubicin's cellular target is Topoisomerase II (Top2) (Tewey et al., 1984). It binds both DNA and Top2 to form the ternary Top2-doxorubicin-DNA cleavage complex, which triggers cell death. There are two Top2 enzymes, Top2a and Top2b. Top2a, a known marker of cell proliferation, is over-expressed in tumors but not detectable in quiescent tissues (Capranico et al., 1992, Lyu et al., 2006). Thus, Top2a is thought to be the molecular basis of doxorubicin's anticancer activity.
Doxorubicin was postulated to induce cardiotoxicity through redox-cycling and generation of reactive oxygen species (ROS) (Singal et al., 1998). The ROS hypothesis, however, has been tempered by a series of studies in which ROS scavenger treatment failed to prevent cardiac toxicity caused by doxorubicin (Myers et al., 1983, Martin et al., 2009). Thus, the mechanism cardiotoxicity caused by anthracyclines, such as doxorubicin, has remained elusive and to date there is no method available to predict whether a patient will develop heart damage as a result of an anthracycline-based therapy.